Diagnostic Criteria for the Asthma-COPD Overlap (ACO) Still Room for Improvement-Juniper publishers
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Introduction
Chronic obstructive pulmonary disease (COPD) is a
heterogeneous disease in which the clinical presentation and prognosis
vary according to the phenotype [1]. In the last years, one of the
phenotypes of COPD, that is recognized as the Asthma-COPD Overlap (ACO)
has received increasing attention.
In contrast with the remaining COPD phenotypes,
patients with ACO present an elevated reversibility of airflow
obstruction as well as a greater degree of eosinophilic bronchial
inflammation, thereby demonstrating greater response to inhaled
corticosteroid (ICS) treatment [2-4]. These characteristics are
suggestive of asthma and can be explained by a history of asthma during
youth being an independent risk factor for the development of COPD in
smokers [5] (Figure 1).
From a clinical point of view, patients with ACO
present more symptoms, have a worse quality of life and a higher risk of
exacerbations than the remaining patients with COPD, but they have a
better survival. In the CHAIN study including125 COPD patients labeled
as having ACO and who fulfilled specific characteristics associated with
asthma according to some diagnostic criteria [major criteria:
bronchodilator test (BDR)>400ml and 15%or a history of asthma; minor
criteria: eosinophilia >5%, IgE> 100IU/ml or two BDR>200ml and
12 %] were found to have a greater one year survival compared to the
remaining patients with COPD without ACO [6].
Likewise, the cohort study by Hokkaido followed 268
patients labeled as having ACO who did not have a previous diagnosis of
asthma but fulfilled the characteristics of asthma (reversibility of
airflow obstruction ≥12 % and 200 ml, eosinophilia ≥300 eosinophils/μl
and/or atopy (specific IgE positive for at least one inhaled antigen),
and it was observed that despite these patients presenting a worse score
in the St. George quality of life questionnaire, they had a lower
mortality at 10 years compared to non ACOS patients probably because of
greater response to anti inflammatory treatment with ICS [7].
Globally, the prevalence of ACOS reported varies
greatly due to the different diagnostic criteria used. Different
epidemiological studies in which ACOS is defined as patients with COPD
diagnosed with asthma before the age of 40 described prevalences of 13%
and 17% [6,8]. Using the same definition, a multicenter,
cross-sectional, observational study carried out in Spain including 3125
patients with COPD in primary care and specialized centers reported a
prevalence of ACO of 15.9% [9]. The prevalence of ACO was determined to
be between 1.6 and 4.5% in the general adult population and between 15%
and 25 % in the adult population with COPD.
In the last years attempts have been made to define
the diagnostic criteria of this phenotype, but no definitive consensus
has been achieved. In Spain, a diagnostic consensus by the Spanish COPD
Guidelines (GesEPOC) was initially proposed, including very restrictive
criteria in which 2 major criteria or 1 major and 2 minor criteria had
be fulfilled for a patient to be defined as having ACO. The major
criteria included a very positiveBDR≥400ml and 15% compared to baseline,
eosinophilia in sputum and a personal history of asthma (prior to 40
years of
age), and the minor criteria were an elevated total IgE, a history
of atopy and a positive BDR ≥200ml and 12% on at least two
occasions [10]. Thereafter, an agreement between the Global
Initiative for Asthma (GINA) and the Global initiative for Chronic
Obstructive Lung Disease (GOLD) defined the ACO phenotype as
persistent airflow limitation with characteristics of both asthma
and COPD but did not clearly specify how many criteria should
be met to establish a diagnosis of ACO [11].
Later in 2016, a consensus was made among specialists in
North America, Europe and Asia, proposing 3 major criteria
(persistent airflow limitation <0.70 in patients over 40 years
of age, exposure to smoking of at least 10 packs-year or the
equivalent in biomass smoke exposure, a documented history
of asthma before age 40 or BDR>400ml in FEV1) and 3 minor
criteria (documented history of atopy or allergic rhinitis,
BDR≥200ml and 12%on at least 2 occasions, peripheral
eosinopilia ≥300eosinophils/μL). For a diagnosis of ACO, 3
major criteria and at least one of the minor criteria proposed
had to be met [12].
More recently, the new consensus between GesEPOC and
the Spanish Guidelines for the Management of Asthma (GEMA)
defined overlapping of asthma and COPD (ACO) as the presence
of chronic persistent airflow limitation, in a smoker or former
smoker [tobacco exposure≥10 pack-years] with a concomitant
diagnosis of asthma or with characteristics of asthma such as
very positive BDR (≥15% and ≥400ml) and/or blood eosinophilia
(≥300 eosinpophils/μL). Thus, the ACO phenotype includes not
only smoker asthma patients who develop persistent airflow
obstruction but also COPD with characteristics of asthma. To
fulfill this definition, airflow limitation must be persistent over
time, current or past smoking should be the main risk factor,
and the patient must present clinical, biological or functional
characteristics of asthma [13].
The diagnosis is sequential; the presence of chronic airflow
obstruction must first be confirmed with a post bronchodilator
FEV1/FVC ratio<0.70 in patients over 35 years of age who are
active or former smokers of at least 10 pack-years. In cases of
doubtful diagnosis, the patients should undergo spirometry
evaluation after at least 6 months of treatment with an ICS
and a long-acting β2 agonist (LABA). In case of reversibility of
airflow obstruction the diagnosis is asthma. After confirming the
persistence of chronic airflow obstruction, the current diagnosis
of asthma should be confirmed by a family or personal history
or asthma and/or atopy with respiratory symptoms (wheezing,
cough, chest oppression) or upper airway inflammation or
daily variability of PEF≥20% or exhaled nitric oxide fraction
(FENO≥50ppb). If the diagnosis of asthma cannot be established,
the diagnosis of ACO is confirmed if a patient with COPD presents
features of asthma: a very positive PBD (≥15% and ≥400ml) and/or the presence of eosinophilia in blood (≥300 eosinophils/
μL) [13].
Eosinophilia has shown to be a good biomarker to identify
COPD patients showing better response to ICS treatment who
fulfill the ACO criteria. However, the cut-off value is controversial.
In one study comparing stable COPD patients without ACO
with another stable COPD group with ACO, the patients with
ACO presented blood eosinophil concentrations double
those observed in the COPD group without ACO [14]. Studies
comparing eosinophilc inflammation in blood and sputum have
suggested that a cut-off value of ≥300eosinophils/μLin blood
is a good predictor of eosinophilia in sputum [15]. Different
consensuses recommend this cut-off of ≥300 eosinophils/μL in
peripheral blood [12,13].
With regard to the treatment of patients fulfilling ACO
criteria, the objectives are to prevent exacerbations as well as
maintain acceptable control of the symptoms and reduce the
grade of bronchial obstruction. The importance of diagnosing
ACO is to identify patients with COPD who require treatment
with ICS plus LABA from early phases of the disease.
Thus, the new GesEPOC-GEMA consensus establishes a
combination of LABA/ICS as the initial treatment. However, a
combination of choice cannot be recommended since no study
has compared different combinations [13]. Therefore, the
elevated doses of ICS currently recommended for the treatment
of COPD are associated with a greater incidence of adverse
effects, and a dose-response relationship with clinical efficacy
has not been demonstrated. Thus, intermediate doses of ICS are
recommended for the maintenance of these patients [16].
In more severe cases a long-acting anti cholinergic (LAMA)
may be added, constituting triple therapy (LABA/ICS/LAMA).
Although in the future some of these patients, particularly
the most severe not controlled with triple therapy, may be
candidates to treatment with new biological drugs, there are no
specific clinical trials on patients with ACO with this particular
phenotype.
Likewise, smoking cessation should be insisted upon as
should respiratory rehabilitation and the use of nasal anti
inflammatories and oxygen therapy in indicated cases [13].
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